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Running interference on miR-33: a new amplification loop for type I interferon in the host antiviral response

Cellular & Molecular Immunology volume 17, pages 1109–1110 (2020)Cite this article

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Innate immunity is the first line of host defense against viral infections. Mitochondria, best known as the cell’s “power plant” for ATP generation, have recently been shown to serve as essential platforms for the signaling events that induce antiviral type I interferon (IFN). Localization of the adaptor mitochondrial antiviral signaling protein (MAVS) to the mitochondrial surface via a C-terminal transmembrane domain is required for RIG-I-like receptors (RLRs) to transduce antiviral signaling upon detection of double-stranded RNA in the cytosol. Mitochondrial quality control through autophagy (i.e., mitophagy) can impact RLR/MAVS signaling through effects on mitochondrial mass and function.1 Previous studies have generally indicated that mitophagy promotes virus infection by decreasing RLR/MAVS signaling and downstream type I IFN production.2 Viruses can interestingly coopt this housekeeping function for their benefit, as viral proteins translocate to mitochondria, accelerate mitophagy through attenuation of mitochondrial membrane potential, and thereby suppress RIG-I signaling.3 MAVS signaling to type I IFN can also be regulated by mitochondrial dynamics through fusion and fission, whereby MAVS expression promotes fission, while fission inhibits MAVS.4 Finally, type I IFNs have recently themselves been shown to prime antiviral responses in part through reprogramming mitochondrial metabolism, suggesting the existence of complex feedback loops.5

MicroRNA (miR)-33, which is located within an intron of the cholesterol synthesis transcriptional regulator sterol-regulatory element–binding factor–2 (Srebf2), has recently been identified as a master coordinator of cell metabolism and host defense. First identified for its inhibition of cellular cholesterol efflux through its targeting of lipid efflux transporters for degradation,6 miR-33 has since been shown to skew cellular bioenergetics away from mitochondrial fatty acid oxidation and toward glycolysis.6,7 miR-33 also directly targets for degradation ATG5, ATG12, MAP1LC3B, LAMP1, and PRKAA1 in the autophagy pathway.7,8 Interestingly, in addition to its co-induction along with Srebf2 in response to metabolic cues (i.e., low cholesterol), miR-33 is responsive to inflammatory and infectious stimuli, including bacterial lipopolysaccharide and IFN-γ. M. tuberculosis (Mtb) upregulates miR-33 in airway macrophages, thereby preventing autophagic killing (i.e., xenophagy) and accumulating lipid bodies for its own nutrient source; conversely, pharmacological silencing of miR-33 promotes Mtb clearance from the host.8

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References

  1. Zhang, L., Qin, Y. & Chen, M. Viral strategies for triggering and manipulating mitophagy. Autophagy 14, 1665–1673 (2018).

    Article  CAS  Google Scholar 

  2. Xia, M. et al. Mitophagy enhances oncolytic measles virus replication by mitigating DDX58/RIG-I-like receptor signaling. J. Virol. 88, 5152–5164 (2014).

    Article  Google Scholar 

  3. Yoshizumi, T. et al. Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. Nat. Commun. 5, 4713 (2014).

    Article  CAS  Google Scholar 

  4. Castanier, C., Garcin, D., Vazquez, A. & Arnoult, D. Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. EMBO Rep. 11, 133–138 (2010).

    Article  CAS  Google Scholar 

  5. Wu, D. et al. Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 44, 1325–1336 (2016).

    Article  CAS  Google Scholar 

  6. Rayner, K. J. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328, 1570–1573 (2010).

    Article  CAS  Google Scholar 

  7. Ouimet, M. et al. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J. Clin. Invest 125, 4334–4348 (2015).

    Article  Google Scholar 

  8. Ouimet, M. et al. Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism. Nat. Immunol. 17, 677–686 (2016).

    Article  CAS  Google Scholar 

  9. Liu, D. et al. MicroRNA-33/33* inhibit the activation of MAVS through AMPK in antiviral innate immunity. Cell Mol. Immunol. https://doi.org/10.1038/s41423-019-0326-x (2019).

  10. Rayner, K. J. et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478, 404–407 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01 ES102005), National Institutes of Health.

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  1. Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA

    Fei Zhao & Michael B. Fessler

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  1. Fei Zhao
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Correspondence to Michael B. Fessler.

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Zhao, F., Fessler, M.B. Running interference on miR-33: a new amplification loop for type I interferon in the host antiviral response. Cell Mol Immunol 17, 1109–1110 (2020). https://doi.org/10.1038/s41423-020-0373-3

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